DETAILED ACTION
Notice of Pre-AIA or AIA Status
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
Summary
Claims 1-7 and 10 are pending in this office action. Claims 8-9 are cancelled. All pending claims are under examination in this application.
Priority
The current application was filed on June 7, 2024 is a 371 of PCT/CN2022/137518 filed on December 8, 2022. The current application claims foreign priority to CN202111498028.9 filed on December 9, 2021.
Information Disclosure Statement
Receipt of the Information Disclosure Statement filed on June 7, 2024 is acknowledged. A signed copy of the document is attached to this office action.
Claim Objections
Claims 1-7 and 10 are objected to because of the following informalities:
Claim 1: Please insert “Formula I” below the structure within claim 1. Furthermore, please insert an “and” into the text, “…for imaging and diagnosing…”
Dependent claims 2-7 and 10 are included here because they fail to cure the defects of claim 1.
Claim 4: Please amend the text of the claim to read, “… a phenyl ring or a thiazole ring.”
Claim 7: Please use a subscript to define “m” (in both cases) and move it adjacent to the close portion of the bracket (for example, TsO-(CH2)m-O- instead of TsO-(CH2) m-O-). Also, please define the acronyms “Ts” and “Ms” in-full.
Claim 10: Please insert an “and” into the text, “…for imaging and diagnosing…” Also, please add the symbol for “a” instead of “a” prior to synuclein.
Appropriate correction is required.
Claim Rejections - 35 USC § 112
The following is a quotation of 35 U.S.C. 112(b):
(b) CONCLUSION.—The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the inventor or a joint inventor regards as the invention.
The following is a quotation of 35 U.S.C. 112 (pre-AIA ), second paragraph:
The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the applicant regards as his invention.
Claims 2-5 and 10 are rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention.
Claims 2-5 use the term “preferably.” The text "preferably" renders the claim indefinite because it is unclear whether the limitations following the phrase are part of the claimed invention. See MPEP § 2173.05(d).
Claim 10 is rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph. Claim 10 is written as a “use” claim and does not recite process steps. Additionally, claim 10 does not comply with the four statutory categories. It is therefore, indefinite.
Claim Rejections - 35 USC § 101
35 U.S.C. 101 reads as follows:
Whoever invents or discovers any new and useful process, machine, manufacture, or composition of matter, or any new and useful improvement thereof, may obtain a patent therefor, subject to the conditions and requirements of this title.
Claim 10 is directed to non-statutory subject matter. The claim 10 does not fall within at least one of the four categories of patent eligible subject matter because it is written as a “use” claim.
Claim Rejections - 35 USC § 103
In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis (i.e., changing from AIA to pre-AIA ) for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
The factual inquiries for establishing a background for determining obviousness under 35 U.S.C. 103 are summarized as follows:
1. Determining the scope and contents of the prior art.
2. Ascertaining the differences between the prior art and the claims at issue.
3. Resolving the level of ordinary skill in the pertinent art.
4. Considering objective evidence present in the application indicating obviousness or non-obviousness.
This application currently names joint inventors. In considering patentability of the claims the examiner presumes that the subject matter of the various claims was commonly owned as of the effective filing date of the claimed invention(s) absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and effective filing dates of each claim that was not commonly owned as of the effective filing date of the later invention in order for the examiner to consider the applicability of 35 U.S.C. 102(b)(2)(C) for any potential 35 U.S.C. 102(a)(2) prior art against the later invention.
Claims 1-7 and 10 are rejected under 35 U.S.C. 103 as being unpatentable over Ye et al. (CN112645891A) in view of Paul et al. (Adv. Synth. Catal., 2017), and Liu et al. (Drug Design, Development and Therapy, 2016).
[The Examiner is going to introduce each reference and then combine them where appropriate to reject the instant claims.]
1. Ye et al.
Ye et al. is the closest prior art to the present invention as it teaches small molecule compound bonded with alpha-synuclein aggregate, and preparation method and application thereof (see title). Additionally, Ye et al. disclose that the invention belongs to the technical field of medicine and relates to a compound capable of being bonded with alpha-synuclein aggregate, and a preparation method and application thereof. The structural general formula of the compound is shown in the formula I, wherein m is a positive integer selected from 1 to 3, R1 is respectively selected from phenyl, substituted phenyl, naphthyl, biphenyl, 5-6-membered aromatic heterocycle and substituted 5-6-membered aromatic heterocycle, and R2 is selected from benzyl, C1-3 alkyl naphthyl, C1-3 alkyl, phenyl, substituted phenyl, 5-6-membered heteroaromatic ring and substituted 5-6-membered heteroaromatic ring. The compound disclosed by the invention can be strongly bonded with alpha-synuclein aggregate, can be used as an imaging tracer agent required by image examination technologies such as PET (Polyethylene Terephthalate) and SPECT (Single Photon Emission Computed Tomography) for clinical disease diagnosis or used for preparing the imaging tracer agent and preparing a composition comprising the imaging tracer agent, and used for detecting diseases related to alpha-synuclein misfolding and abnormal aggregation, such as Parkinson's disease, and has a remarkable good application prospect (see abstract).
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2. Paul et al.
Paul et al. teach transition metal-free iodosobenzene-promoted direct oxidative
3-arylation of quinoxalin-2(H)-ones with arylhydrazines (see title). In addition, Paul et al. disclose a transition metal-free iodosobenzene promoted direct oxidative 3-arylation of quinoxalin-2(H)-ones was developed using various arylhydrazines under air. The protocol affords a variety of 3-arylquinoxalin-2(H)-one derivatives in moderate to good yields. This method provides a rapid access to biologically interesting benzo[g]quinoxalinones and pyrido[3,4-b]pyrazinones. The present methodology features high functional group tolerance including base-sensitive groups as well as allyl- and benzyl substituted quinoxalin-2(H)-ones under mild reaction conditions (see abstract).
3. Liu et al.
Liu et al. teach design, synthesis, and biological evaluation of 3-
vinyl-quinoxalin-2(1H)-one derivatives as novel antitumor inhibitors of FGFR1 (see title). Furthermore, Liu et al. disclose FGFR1 is well known as a molecular target in anticancer drug design. TKI258 plays an important role in RTK inhibitors. Utilizing TKI258 as a lead compound that contains a quinazolinone nucleus, we synthesized four series of 3-vinyl-quinoxalin-2(1H)-one derivatives, a total of 27 compounds. We further evaluated these compounds for FGFR1 inhibition ability as well as cytotoxicity against four cancer cell lines (H460, B16-F10, Hela229, and Hct116) in vitro. Some compounds displayed good-to-excellent potency against the four tested cancer cell lines compared with TKI258. Structure-activity relationship analyses indicated that small substituents at the side chain of the 3-vinyl-quinoxalin-2(1H)-one were more effective than large
substituents. Lastly, we used molecular docking to obtain further insight into the interactions between the compounds and FGFR1 (see abstract).
Combination of Ye et al., Paul et al., and Liu et al.
Regarding instant claim 1, Ye et al., Paul et al., and Liu et al. teach a compound represented by general Formula I, its pharmaceutically acceptable salt or solvate, which can be used as a tracer for the imaging diagnosis of a-synuclein accumulation diseases. The necessary citations within Ye et al., Paul et al., and Liu et al. that pertain to instant claim 1 are presented in Table I.
Table I
Instant Claim 1
Ye et al., Paul et al., and Liu et al. Citations
A compound represented by general Formula I, its pharmaceutically acceptable salt or solvate, which can be used as a tracer for the imaging and diagnosis of a-synuclein accumulation diseases,
Ye et al. disclose a small molecule compound capable of strongly binding to an a-synuclein aggregate, a preparation method therefor and application thereof in medicine. The compound of the present invention can be used as an imaging tracer required by a clinical disease diagnosis image examination technology, or is used for preparing the image imaging tracer, and preparing a composition comprising the imaging tracer, for the imaging and diagnosis of diseases associated with abnormal aggregation of a-synuclein, such as Parkinson's disease, Alzheimer's disease and the like, wherein the structural formula of the compound I-1 is as follows:
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(see title, abstract, claims, and paragraphs [0011] and [0024] within Ye et al.).
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Ye et al. disclose all of the instant claim 1 for R1, R3, and R4. But it does not disclose the substituents of R2. However, both Paul et al. disclose analogues of quinoxalin-2(H)-ones having R2 substitutions.
Specifically, Paul et al. disclose the “western” aryl ring substitution:
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(see Table 3 within Paul et al.).
Liu et al. disclose derivatives of the following variation similar to Ye et al.:
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(see Figure 2 and Figure 3 within Liu et al.).
It would have been obvious to one of ordinary skill in the art prior to the effective filing date of the claimed invention to modify Ye et al. with the teachings of both Paul et al. and Liu et al. to create a medicinal chemistry compound library of quinoxalin-2(H)-ones that strongly bind to an a-synuclein aggregate. The motivation would be to fully explore the structure-activity relationship (SAR) on the “western” aryl ring in order to arrive at a preclinical candidate within the a-synuclein aggregate binding series.
Regarding instant claim 2, Ye et al., Paul et al., and Liu et al. teach wherein R1 is preferably pyridyl.
Ye et al. disclose the pyridyl variant, I-28:
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A skilled artisan (POSITA; person having ordinary skill in the art) would substitute pyridyl moieties for aryl rings such as the one seen in analogue I-1. Despite the ring A and R3 and R4 moieties not being in agreement with instant claim 1, the substitution of the pyridyl group for an aryl group is disclosed by Ye et al. and thus be applied within the series. Substitution of a heterocycle for an aryl group is standard protocol in determining the SAR surrounding a target molecule.
Regarding instant claim 3, Ye et al., Paul et al., and Liu et al. teach wherein R3 and R4 are preferably methyl.
Ye et al. disclose derivative I-1 (see instant claim 1) having the desired methyl substitution at R3 and R4.
Regarding instant claim 4, Ye et al., Paul et al., and Liu et al. teach wherein ring A is preferably phenyl ring or thiazole ring. Ye et al. disclose derivative I-1 (see instant claim 1) having the desired phenyl substitution of the A ring.
Regarding instant claim 5, Ye et al., Paul et al., and Liu et al. teach wherein one or more atoms of the compound of Formula I are the radioisotopes of that atom, of which preferably taken from 11C, 13N, 15O, 18F, 76Br, 123I, 125I, and 131I.
Ye et al. disclose that the compounds of this invention can be used as imaging tracers required for clinical disease diagnosis imaging techniques, or for preparing such imaging tracers, as well as for preparing compositions including such imaging tracers, to diagnose diseases related to abnormal aggregation of a-synuclein, such as Parkinson's disease and Alzheimer's disease (see paragraph [n0001] within Ye et al.). As such, a skilled artisan (POSITA) could identify radioisotopes that could be used based on the substitution pattern of the analogue within the quinoxalin-2(H)-one series [11C, 13N, 15O, 18F, 76Br, 123I, 125I, and 131I].
Regarding instant claims 6 and 7, Ye et al., Paul et al., and Liu et al. teach wherein the compound represented by Formula I is selected from the following structures of instant claim 6.
The aryl fluoride (R2) analogue in which the methyl substitution at R3 and R4 are all isotopically labeled would be an obvious variant in light of the Ye et al., Paul et al., and Liu et al. disclosures (see the discussion and citations within instant claim 1; I-1 from Ye et al.; and 4c from Paul et al.).
Regarding instant claim 10, Ye et al., Paul et al., and Liu et al. teach the use of a compound represented by general Formula I, its pharmaceutically acceptable salt, or solvate thereof according to instant claim 1, in the preparation of a tracer for imaging diagnosing a-synuclein accumulation diseases, wherein the compound or its pharmaceutically acceptable salt or solvate thereof can bind to a-synuclein aggregates.
Ye et al. disclose the use of the compound that binds to a-synuclein aggregates
according to any one of claims 1-5 in the preparation of an imaging tracer and in the preparation of a composition comprising the imaging tracer (see claim 8 within Ye et al.). Additionally, Ye et al. disclose the use according to claim 8 is characterized in that the imaging tracer and the composition including the imaging tracer are used to detect disease symptoms related to a-synuclein misfolding and aggregation; the imaging tracer is an imaging tracer required for use as an imaging examination technique for clinical disease diagnosis (see claim 9 within Ye et al.).
Analogous Art
The Ye et al., Paul et al., and Liu et al. references are directed to the same field of endeavor as the instant claims, that is, a compound represented by general Formula I, its pharmaceutically acceptable salt or solvate, which can be used as a tracer for the imaging and diagnosis of a-synuclein accumulation diseases, as disclosed within instant claim 1.
Obviousness Analysis
It would have been prima facie obvious to one of ordinary skill in the art prior to the effective filing date of the claimed invention to modify quinoxalin-2(H)-ones disclosed by Ye et al., using the teachings of Paul et al. and Liu et al. in order to arrive at the subject matter of the instant claims.
The Ye et al., Paul et al., and Liu et al. references all have considerable overlap in the quinoxalin-2(H)-one arts. In this instance, Ye et al. supplies the template for the quinoxalin-2(H)-one targets as it pertains to imaging and diagnosing, Paul et al. supplies a disclosure for the substitution of the “western” aryl ring, while Liu et al. supplies the general support for the quinoxalin-2(H)-one derivatives. All references are directed to quinoxalin-2(H)-ones and therefore constitute analogous art under MPEP §2141.01(a). A POSITA would have reasonably consulted the three references when seeking to develop a candidate within the quinoxalin-2(H)-one series.
Given these teachings, a POSITA would have been motivated to combine the template for the quinoxalin-2(H)-ones as disclosed by Ye et al., the required “western aryl substitution supplied by Paul et al., and the general support for the quinoxalin-2(H)-one analogues disclosed by Liu et al.
The modification constitutes a simple substitution of one known element for another to obtain a predictable result [MPEP §2143(I)(B)].
The combination represents the use of a known technique to improve a similar composition in the same way [MPEP §2143(I)(C)].
The art provides a finite number of identified, predictable solutions, and the POSITA would have pursued the claimed configuration with a reasonable expectation of success [MPEP §2143(I)(E); KSR].
The combination of the quinoxalin-2(H)-ones taught by Ye et al. along with the use of the necessary claim limitations taught by Paul et al. and Liu et al. would allow a research and development scientist (POSITA) to develop the invention taught in the instant application.
Furthermore, the additional claim limitations taught by Paul et al. and Liu et al. would have been viewed by a POSITA as routine design optimizations or known modifications for quinoxalin-2(H)-ones. The motivation would be to fully explore the structure-activity relationship (SAR) on the “western” aryl ring in order to arrive at a preclinical candidate within the a-synuclein aggregate binding series in order to arrive at a preclinical candidate. Implementing these features in Ye et al.’s quinoxalin-2(H)-ones would not require more than ordinary skill or routine experimentation.
Accordingly, the combination of Ye et al., Paul et al., and Liu et al. provides all the elements of the claimed invention. The resulting quinoxalin-2(H)-ones, constitute no more than the predictable outcome of combining familiar prior art components, and therefore the claimed subject matter would have been obvious to a POSITA prior to the effective filing date of the invention.
Conclusion
No claims are allowed.
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/JOHN W LIPPERT III/Examiner, Art Unit 1615
/Robert A Wax/Supervisory Patent Examiner, Art Unit 1615
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